Study on chromosome ends may aid cancer research

PRINCETON, N.J. -- A Princeton scientist has discovered a
mechanism that cells use to control the length of their chromosome
ends, a process that is thought to go awry in cancer.

The finding, reported in the August 4 issue of Science by
Professor of Molecular Biology Virginia Zakian and colleagues, may
provide cancer researchers with clues for designing
treatments.

Zakian found a naturally occurring protein that inhibits the
activity of another protein, called telomerase, which replicates
and lengthens the very ends of chromosomes. The protein, called
Pif1p, acts directly on the chromosome ends, called telomeres, to
keep the lengthening process in check, Zakian's research group
reported.

Researchers have been studying telomerase with great intensity
for the past 15 years because it appears to play a central role in
the way cells age or become cancerous. Studies have shown that
telomerase is present in 90 percent of cancer types, but is absent
from most healthy cells. Cancer researchers have thus looked for
ways to interfere with telomerase. Zakian's research suggests that
mimicking or enhancing the action of Pif1p may be a good way to do
so.

Telomerase builds structures called telomeres at the ends of
chromosomes, like plastic caps at the ends of shoelaces. In normal
conditions, telomeres shorten each time a cell divides, eventually
exposing the genetic material and causing the cell to die. In
cancer cells, however, telomerase keeps rebuilding the telomere
caps, preventing the cell from undergoing its normal aging
process.

In 1994, Zakian and collaborator Vincent Schulz reported that
Pif1p keeps telomeres from lengthening. It remained unclear,
however, how Pif1p accomplished that feat. There are many natural
substances that could inhibit telomere lengthening in indirect
ways,

Zakian said. The new paper shows that Pif1p acts on the
telomerase pathway itself and interacts directly with telomeric
DNA, a potentially attractive feature for drug developers.

One interesting aspect of Pif1p is that it is special type of
enzyme, a helicase, that unwinds the double strands of DNA.
Zakian's research team created a small mutation in the gene that
encodes Pif1p so that the protein is produced normally yet lacks
this unwinding ability. When telomerase-rich cells carried this
mutated gene, Pif1p no longer worked and telomere lengthening
progressed unchecked. Zakian believes that Pif1p may work by
unzipping a temporary bond that forms between telomerase and the
chromosome as telomeres are synthesized.

The experiments were done in baker's yeast cells, but Zakian
said that telomere regulation has been so important throughout
evolution that human cells employ many of the same mechanisms.

"These are very lowly organisms. This is what we use to bake
bread," she said. "However, as we show in this paper, humans have
a protein very similar to yeast Pif1p. It would be quite
gratifying if it turned out that it also functions in a similar
way in humans and could give us insights into human cancer."